The limitations of chemotherapy and radiotherapy have driven a search for novel ways to prevent and treat cancers. Research teams from around the world have been using Diamond’s world-leading facilities to investigate many new approaches, some of which are described below.
Cancer cells have developed mechanisms to protect themselves from being destroyed by a body’s immune system. Researchers around the world are looking at different ways to overcome these complex mechanisms. An international team of researchers has been investigating the role of the immune receptor Tim-3 and its related protein galectin-9 in shielding breast cancer cells
. They found that breast tumours express significantly higher levels of Tim-3 and galectin-9 than healthy tissue. The team partnered with Diamond scientists and used synchrotron radiation circular dichroism spectroscopy on the B23 beamline to investigate these defence mechanisms. The research also revealed increased levels of these key proteins in nine other cancers, highlighting the important role of the Tim-3-galectin-9 pathway in cancer development. Further research is required to discover the best way to disable the pathway to allow the immune system to attack cancer cells.
Another promising new approach to cancer therapy is the use of monoclonal antibodies (mAbs) to modulate the immune response and improve the body’s ability to destroy cancer cells. To date however use of anti-4-1BB mAbs such as urelumab has been limited due to intolerable side-effects. An international team redesigned a 4-1BB molecule to form a recombinant antibody called a trimerbody
that had potent stimulatory activity with no associated toxicity. They used High Throughput Small Angle X ray Scattering (SAXS) on beamline B21 as part of their research. This novel approach may unlock the potential of immunotherapeutic antibodies in the treatment of cancer with minimal side-effects.
The cyclin-dependent protein kinase (CDK) family are involved in the regulation of the cell cycle and in differentiating cell types. Dysregulation of their activity is associated with inappropriate cell cycle progression and cancer, and so CDKs have been studied intensively as potential anti-cancer targets in certain cancer subtypes. The first generation of these molecules had dose-limiting toxicities. A team of researchers from Newcastle Cancer Centre used macromolecular crystallography techniques on beamlines I03, I04-1 and I04
to distinguish subtle yet profound differences between different CDK sub-types that may allow the unusual properties of CDK1 inhibitors to be used as anti-cancer therapies.
Bromo and extra-terminal (BET) proteins play an important role in cell transcription and such have become attractive pharmaceutical targets in the fight against cancer. A team of researchers from Canadian institutions and Oxford University performed a range of systematic proteomics
, biophysical, structural, and cell biological studies, including macromolecular crystallography on beamlines I02, I03 and I24. These studies provided a framework to better understand BET biochemistry and promote the rational development of new inhibitors.
P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures have been defined, these are either at low resolution, or represent mutated and/or quiescent states of the protein. A study from the University of Manchester using the Titan Krios-I electron microscope in the Electron Bioimaging Centre (eBIC) at Diamond defined new high resolution features of ABCB1
at 8 Angstrom which provided valuable insights into the mechanism of drug stimulation of P-glycoprotein activity. This in turn will aid in the future design of an effective and reversible P-glycoprotein inhibitor to address multi-drug resistance in cancer therapy.
The protein Mcl-1 (myeloid cell leukaemia 1) is associated with cancers of high tumour grade, poor survival and resistance to chemotherapy, and has emerged as an attractive target for cancer therapy. Overexpression of Mcl-1 has been reported in a variety of haematological malignancies and solid tumours and research in this area may apply to a wide range of cancers. An international pharmaceutical company research group
screened a large number of promising compounds to identify selective small molecule inhibitors of Mcl-1 using nuclear magnetic resonance and X-ray derived structural information.
Crystallography was performed on beamlines I03 and I04 at Diamond. These early research efforts have identified a lead compound that is currently undergoing further analysis. Another recent study on Mcl-1 discovered and characterised an antibody fragment
produced in vitro which could be used in future cancer treatment. The study used macromolecular crystallography on beamlines I02, I03, I04 and I04-1 to crystallize the antibody fragment with Mcl-1 enabling ligand-independent crystallization. This early research was vital in supporting the discovery of a new compound AZD5991 which is currently in clinical trials for treating relapsed chronic lymphocytic leukaemia and multiple myeloma.